Are All Our Body Cells the Same?

We all start from a single fertilised egg, growing through countless cell divisions. However, the DNA sequences in our cells don’t remain identical throughout our lives. As we age, errors (mutations) can occur during cell division. If these errors aren’t repaired, they result in a mix of normal and mutated cells. This phenomenon is likened to a mosaic art and is called “somatic mosaicism”.

This isn’t just about genetics. Factors like UV radiation, inflammation, lifestyle habits (i.e., drinking, smoking, stress, and lack of sleep), and the natural decline of repair mechanisms with age can accelerate the mosaicism of our body cells.

When Somatic Cells Become a Mosaic…

Research has revealed that genetic mutations can increase the risk of cancer, heart disease, and even mental disorders. Heart disease, a leading cause of death worldwide, can be particularly severe when mutated blood cells infiltrate the arteries and heart, worsening the condition.

With advancements in detection technologies, uncovering the realities of somatic mosaicism could bring groundbreaking insights across various fields. Why not take this opportunity to dive into the fascinating world of somatic mosaicism?

Title: Somatic Mosaicism in Esophagus, Pharynx, and Buccal Mucosa

Speaker: Akira Yokoyama, M.D., Ph.D.

Senior Lecturer, Department of Medical Oncology, Kyoto University Hospital

Recently, it has been reported that genomic abnormalities accumulate not only in cancer but also in normal tissues due to aging and exposure to various environmental factors, resulting in clonal expansion of cells that have acquired driver mutations for cancer. We reported that in normal esophageal epithelium, clonal expansion of esophageal cancer driver mutations is caused by alcohol consumption and smoking, in addition to aging. The oral cavity, pharynx, and esophagus are commonly composed of squamous epithelium. Drinking and smoking are common risk factors for carcinogenesis in these three organs, and it is known that multiple cancers in the same region can cause field carcinogenesis, and it is assumed that epithelial remodeling by driver mutant clones occurs not only in the esophagus but also in the pharynx and buccal mucosa. Therefore, we attempted to evaluate the degree of exposure to esophageal cancer risk factors such as alcohol consumption and smoking by detecting gene mutation clones in the buccal mucosa. Because the clone size of driver mutations in buccal swabs is small compared to the observed area and conventional sequencing is not sensitive enough to detect them, we used the latest sequencing technology called error-corrected sequencing (ECS) to identify the mutated clones with high sensitivity. We will present our recent research results including clonal expansion of the buccal mucosa as well as clonal expansion of the esophagus and pharynx.

Title: Somatic Mutations in Cancer-Associated Genes in Normal Human Endometrium: Considerations on Prevention and Treatment of Gynecological Diseases including Cancer and Infertility

Speaker: Hirofumi Nakaoka, Ph.D.

Principal investigator, Department of Cancer Genome Research, Sasaki Institute, Sasaki Foundation

Cancer is a disease caused by the accumulation of mutations in DNA. To understand the mechanism of carcinogenesis, it is necessary to clarify the process of DNA alterations in normal cells leading to tumorigenesis. Recently, genome analysis using next-generation sequencers has revealed that somatic mutations of cancer-related genes occur during the aging process in various normal tissues and that cells derived from mutant clones are widely present. Some studies have reported that somatic mutations in cancer-related genes occur in normal cells years to decades before carcinogenesis. In other words, cells with somatic mutations in cancer-related genes are thought to coexist with other cells for a long period of time without becoming cancerous. Morphological characteristics of tissues may be involved in the mechanism of accumulation and proliferation of cell clones with cancer-related gene mutations in the three-dimensional space of tissues. The speaker will introduce the genomic analysis of normal endometrium that they are working on.

Title: Evolutionary Histories of Breast Cancer and Related Clones

Speaker: Tomomi Nishimura, M.D., Ph.D.

Deputy Director, Department of Surgery, Japanese Red Cross Fukui Hospital

There are still many unknowns about the carcinogenic mechanism of breast cancer, especially changes in the early stages of carcinogenesis. We examined genetic mutations in normal mammary cells and obtained results suggesting that the accumulation of mutations in the mammary gland is influenced by life events specific to women, such as menopause and childbirth, in addition to aging. We also focused on breast cancer with surrounding precancerous lesions and succeeded in tracing the evolutionary history of cancer in detail from the early stages of carcinogenesis by analyzing the genomes of cancerous and noncancerous epithelium, respectively. The results showed that der(1;16) translocation, a driver mutation, was acquired around puberty in der(1;16)-positive breast cancer, that the non-cancerous clones that acquired the der(1;16) translocation expanded by several centimeters, and that multiple clonal evolutions occurred among these expanded clones, some of which led to carcinogenesis. The results showed that the noncancerous clones that acquired translocations expanded by several centimeters. These results reveal one aspect of the characteristic carcinogenic mode of der(1;16)-positive breast cancer, which accounts for about 20% of breast cancers, and are expected to lead to the elucidation of the carcinogenic mechanism of breast cancer.

Title: Smoking and Somatic Mosaicism in Normal Bronchial Epithelium

Speaker: Kenichi Yoshida, M.D., Ph.D.

Chief, Division of Cancer Evolution, National Cancer Center Research Institute

Recent genome analysis has revealed that normal cells continuously acquire somatic mutations from the fertilized egg stage, resulting in a mosaic state in each tissue and clonal proliferation associated with the acquisition of driver mutations, leading to future carcinogenesis. In normal bronchial epithelium, mutations accumulate with aging, and smoking has been shown to increase the number of mutations by several thousand per cell. In addition, driver mutations in genes such as TP53, which are frequently observed in lung cancer, also increased, and were thought to be associated with the development of lung cancer. On the other hand, in individuals with a history of smoking, especially in former smokers who had smoked in the past, the number of mutations was found to be close to normal in a small number of cells, suggesting that environmental factors such as smoking may be causing dynamic clonal competition. This talk will review somatic mosaicism in bronchial epithelium and its relationship to smoking.

Watch the 46th Sysmex Scientific Seminar videos here!